The recognition of carbohydrate moieties by cells of the innate immune system is emerging as an essential element in antifungal immunity, but despite the number and diversity of lectins expressed by innate immune cells, few carbohydrate receptors have been characterized. Mincle, a C-type lectin, is expressed predominantly on macrophages, and is here shown to play a role in macrophage responses to the yeast Candida albicans. After exposure to the yeast in vitro, Mincle localized to the phagocytic cup, but it was not essential for phagocytosis. In the absence of Mincle, production of TNF-α by macrophages was reduced, both in vivo and in vitro. In addition, mice lacking Mincle showed a significantly increased susceptibility to systemic candidiasis. Thus, Mincle plays a novel and nonredundant role in the induction of inflammatory signaling in response to C. albicans infection.

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Extracellular signal-related kinases 1 and 2 (ERK1/2) are the final components of the mitogen-activated protein kinase (MAPK) phosphorylation cascade, an integral module in a diverse array of signalling pathways for shaping cell behaviour and fate. More recently, studies have shown that ERK1/2 plays an essential role downstream of immune receptors to elicit inflammatory gene expression in response to infection and cell or tissue damage. Much of this work has studied ERK1/2 activation in Toll-like receptor (TLR) pathways, providing mechanistic insights into its recruitment, compartmentalisation and activation in cells of the innate immune system. In this review, we summarise the typical activation of ERK1/2 in growth factor receptor pathways before discussing its known roles in immune cell signalling with a focus downstream of TLRs. We examine emerging research uncovering evidence of dysfunctional ERK1/2 signalling in inflammatory diseases and discuss the potential therapeutic benefit of targeting ERK1/2 pathways in inflammation.

Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro-and anti-inflammatory functions described. We reveal here that the immune-specific transmembrane adaptor SCIMP is a direct scaffold for Erk1/2 in TLR pathways, with high-resolution, live-cell imaging revealing that SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling. SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production, with these effects being phenocopied by Erk1/2 signaling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro-inflammatory responses in macrophages.

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